Infrastructure for the ClinSeq Project A phase I cohort of 1,500 individuals has been evaluated at the NIH Clinical Research Center for a set of cardiovascular phenotypic features, including, but not limited to, coronary artery calcification, lipid profiles, and blood pressure. Participants were selected to fall within a spectrum of coronary artery calcification from normal to disease phenotype. Participants underwent a clinical evaluation, targeted clinical tests, and blood sample collection for genomic analysis and they will provide baseline information about pertinent health behavior and a family history. Exome sequencing of peripheral blood DNA has been performed on all 1,500. Importantly, ClinSeq(c) subjects are consented for return of results (both research and clinical results) and for re-contact for iterative phenotyping. ClinSeq(c) was designed in a way that will provide the long-term potential for pursuing many different clinical projects. We propose to select subsets of subjects from the ClinSeq(c) dataset, identified by their genomic attributes, explore their phenotypic manifestations, as a new path to understanding genotype-phenotype relationships. Furthermore, we have completed a new phase of recruitment, ClinSeq Phase II, which targeted African Americans, a group that is underrepresented in clinical genomics research. By committing to focused recruitment in the community, we have reached our targeted goal of 500. We are now recruiting blood donors for sequencing in the third phase. Evaluating the pathogenicity of variants identified above. A key challenge is to validate variants identified from sequencing and informatics approaches to determine if they are actually pathogenic. This can be done in a number of ways, including clinical phenotyping and pedigree analysis (as performed in HG300387). For the malignant hyperthermia project, we have convened an expert panel under ClinGen to evaluate all variants in RYR1 for MHS pathogenicity and develop a scoring method for future variants. Supporting other research groups by providing control data and phenotyping of controls. We have made ClinSeq variant data widely and openly accessible via dbSNP and dbGAP. We have also pioneered an extraordinary level of data sharing within the IRP by making all of our variants available to all staff by a web interface, which was launched in the fall of 2017. This has allowed a number of investigators to use our data as a comparison to measure the background frequency of variants is particular genes. This has led to the publication of a number of papers. We have completed deposition of our data into dbGaP. Finally, we measure the success of ClinSeq for the intramural program by the impact of the program on the wider research community. To that end, ClinSeq has served as the foundation for the development of the Intramural Research Program Clinical Center Genomics Opportunity, which has provided, through competitive applications, 1,200 exomes to be used by researchers outside of NHGRI to explore their phenotypes of interest and we are using the ClinSeq incidental findings analysis experience to develop a clinical incidental findings service for the CCGO program. We have completed sequencing of these samples and have met our timelines for this ambitious study. We have published a report summarizing the analysis and return of secondary variants in this cohort.